Hematopoietic stems cells (HSCs) are rare cells of the hematopoietic system with the ability to self-renew and differentiate into all mature blood lineages, thereby sustaining hematopoietic homeostasis and immune function. HSC transplantation therapy has been effectively used to manage hematopoietic malignancies, bone marrow/hematopoietic failure, and immunodeficiency. Baron et al., Arch Med Res 34:528-44, 2003; Giralt, Curr Hematol Rep 3:165-72, 2004; Vollweiler et al., Bone Marrow Transplant 32:1-7, 2003. Despite successful utility of HSCs, several clinical limitations remain. These include availability of allogenic HSC donors and inability to harvest adequate numbers of HSCs per donor. Moscardo et al., Leuk Lymphoma 45:11-8, 2004. Although autologous harvests of HSCs via G-CSF mobilization to the peripheral blood have alleviated some of the clinical burden for allogenic HSC transplantation, many patients remain refractory to mobilization and subsequent HSC reconstitution. Cohena and Nagler, Leuk Lymphoma 44:1287-99, 2003. Ex vivo expansion of HSCs has been suggested as a means to increase the number of available HSCs for autologous or allogenic transplantation. Unfortunately, current methods of ex vivo HSC expansion have not proven to benefit transplanted recipients, and experimental evidence suggests that ex vivo culture of HSCs negatively affects their hematopoietic reconstitution ability. Devine et al., Bone Marrow Transplant 31:241-52, 2003; Shih et al., J Hematother Stem Cell Res 9:621-8, 2000; Srour et al., J Hematother 8:93-102, 1999.
Direct in vivo targeting of patient HSCs would provide a more physiological context to modulate HSC function as an alternative to HSC isolation and ex vivo manipulation. However, the current understanding of extrinsic regulators of HSCs has been derived from studies limited to ex vivo culture systems where HSCs are studied in suboptimal and artificial culture systems. As such, many factors implicated in regulating HSC self-renewal in vitro are not amenable to in vivo use.
Glycogen synthase kinase-3 (GSK-3) is a constitutively active serine/threonine kinase, originally identified as inactivating glycogen synthase. Frame and Cohen, Biochem J 359:1-16, 2001; Cohen, Biochem Soc Trans 7:459-80, 1979; Embi et al., Eur J Biochem 107:519-27, 1980. Inhibition of GSK-3 has been implicated in regulation of several pathways, including Wnt, Hedgehog, and Notch. Behrens et al., Science 280:596-599, 1998; Yost et al., Genes Dev 10: 1443-1454, 1996; Jia et al., Nature 416:548-552, 2002; Foltz et al., Curr Biol 12:1006-1011, 2002; Espinosa et al., J Biol Chem 278:32227-35, 2003. Important to HSCs, these same pathways have recently been associated with HSC function by either forced ectopic overexpression of key upstream regulators of these pathways, or ligand presentation in vitro. Murdoch et al., PNAS 100:3422-3427, 2003; Reya et al., Nature 423:409-14, 2003; Bhardwaj et al., Nat Immunol 2:172-80, 2001; Karanu et al., J Exp Med 192:1365-72, 2000; Karanu et al., Blood 97:1960-7, 2001; Cline et al., Diabetes 51:2903-2910, 2002; Ring et al., Diabetes 52:588-595, 2003.
Degenerative muscle diseases, such as muscular dystrophy (MD) include a group of genetic diseases characterized by progressive weakness and degeneration of the skeletal muscles which control movement. There is no specific treatment for any of the forms of MD. Respiratory therapy, physical therapy to prevent painful muscle contractures, orthopedic appliances used for support, and corrective orthopedic surgery may improve the quality of life in some cases. Myopathy is a neuromuscular disorder in which the primary symptom is muscle weakness due to dysfunction of muscle fiber. Treatments for the myopathies depend on the disease or condition and specific causes. Supportive and symptomatic treatment may be the only treatment available or necessary for some disorders.
Regulators of hematopoietic stem cells (HSCs), stem cells, that elicit their effects in vivo have not been identified, limiting clinical manipulation of HSCs to ex vivo systems. Regulators of muscle progenitor cells or neural progenitor cells for in vivo treatment of degenerative muscle diseases or neurodegenerative diseases have not been identified. A need exists in the art for an improved therapy involving hematopoietic stem cell for treatment of immune related disease, and for an improved therapy involving stem cells, muscle progenitor cells or neural progenitor cells for treatment of degenerative muscle diseases or neurodegenerative diseases.